Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation
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Fuad Bahram1,2,5,*, Per Hydbring1,6,*, Susanna Tronnersjö1,7,*, Siti Mariam Zakaria1, Oliver Frings3, Sara Fahlén1,8, Helén Nilsson1,9, Jacob Goodwin1, Natalie von der Lehr2,10, Yingtao Su1,11, Bernhard Lüscher4, Alina Castell1, Lars-Gunnar Larsson1
1Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
2Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
3Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
4Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany
5Moreinx AB, Uppsala, Sweden
6Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
7GE Healthcare, Uppsala, Sweden
8Department of Neuroscience, Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden
9Center for Molecular Pathology, Lund University, Lund, Sweden
10NatScience, Uppsala, Sweden
11Anxun International Co., Limited, Hong Kong, China
*These authors contributed equally to this work
Lars-Gunnar Larsson, e-mail: Lars-Gunnar.Larsson@ki.se.
Keywords: oncogene, tumor suppressor gene, ubiquitin-proteasome system, interferon-gamma, the cancer genome atlas
Received: August 05, 2015 Accepted: November 21, 2015 Published: December 20, 2015
The Myc oncoprotein is tightly regulated at multiple levels including ubiquitin-mediated protein turnover. We recently demonstrated that inhibition of Cdk2-mediated phosphorylation of Myc at Ser-62 pharmacologically or through interferon (IFN)-γ-induced expression of p27Kip1 (p27) repressed Myc’s activity to suppress cellular senescence and differentiation. In this study we identified an additional activity of p27 to interfere with Myc independent of Ser-62 phosphorylation. p27 is required and sufficient for IFN-γ-induced turnover of Myc. p27 interacted with Myc in the nucleus involving the C-termini of the two proteins, including Myc box 4 of Myc. The C-terminus but not the Cdk2 binding fragment of p27 was sufficient for inducing Myc degradation. Protein expression data of The Cancer Genome Atlas breast invasive carcinoma set revealed significantly lower Myc protein levels in tumors with highly expressed p27 lacking phosphorylation at Thr-157 - a marker for active p27 localized in the nucleus. Further, these conditions correlated with favorable tumor stage and patient outcome. This novel regulation of Myc by IFN-γ/p27KIP1 potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc.
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